US3133068A - 5-substituted dibenz[b, f] azepine compounds - Google Patents

5-substituted dibenz[b, f] azepine compounds Download PDF

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Publication number
US3133068A
US3133068A US832498A US83249859A US3133068A US 3133068 A US3133068 A US 3133068A US 832498 A US832498 A US 832498A US 83249859 A US83249859 A US 83249859A US 3133068 A US3133068 A US 3133068A
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Prior art keywords
iminostilbene
piperazino
acid
general formula
parts
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Expired - Lifetime
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US832498A
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English (en)
Inventor
Schindler Walter
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Novartis Corp
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Geigy Chemical Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines
    • C07D223/22—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines
    • C07D223/24—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines with hydrocarbon radicals, substituted by nitrogen atoms, attached to the ring nitrogen atom
    • C07D223/26—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines with hydrocarbon radicals, substituted by nitrogen atoms, attached to the ring nitrogen atom having a double bond between positions 10 and 11

Definitions

  • alkylene represents a 2-6 carbon alkylene chain separating the adjacent nitrogen atoms to which it is attached by at least two carbon atoms
  • j R represents a lower alkyl, lower alkanoyloxyalkyl or lower hydroxalkyl radical
  • R is the methyl, hydroxyethyl or acetoxyethyl radical and alkylene is the 1.3-propylene radical (trimethylene radical).
  • the new compounds are produced by reacting an iminostilbene of the general formula /NY clan-0H2 (III) wherein Y represents a low molecular alkyl or alkanoyl- HO-alkylene-N Riehen, near Basel, Switzerland, as-
  • sodium amide, lithium amide, potassium amide, sodium, lithium or potassium are suitable acid binding agents; and the alkali metal compounds are suit able as metal compounds of the iminostilbenes.
  • the halides also for example, aryl sulphonic acid esters and alkali metal salts of acid sulphuric acid esters are used as reactive esters of amino alcohols of the general Formula III; in particular can be named: [3-(4-rnethyl-piperazino) -ethyl chloride, fl-(4-isopropyl-piperazino) -ethyl chloride, ,3-(4-allyl-piperazino) -ethyl chloride, fl-(4-ethyl-piperazino)-propyl chloride, 6-(4-isobutyl-piperazino)-propyl chloride, -(4-methyl-piperazino) -propyl chloride, 'y-(
  • Iminostilbene and 3.7-dichloro-iminostilbene are the starting compounds of general Formula 11. They are obtained from irninodibenzyl or 3.7-dichloro-iminodibenzyl respectively by converting them into the N-acyl derivatives which canbe easily split, halogenating, for example with bromosuccinimide, splitting oif hydrogen halide and hydrolyzing.
  • alkylene-OH (IV) wherein alkylene and X have the meanings given above, in particular an ester of a halogen hydracid or aryl sulphonic acid, with an N-substituted piperazine of the 'general formula:
  • Starting materials of the general Formula IV are ob tained for example, by reacting alkali metal compounds of iminostilbenes of the general Formula II with reactive diesters of alkandiols, in particular those with two different acid components such as, for example u-bromofi-chloralkanes, o-bromo-w-chloralkanes, aryl sulphonic acid esters of chloralkanols and bromalkanols as well as alkali metal salts of acid chloralkyl and bromalkyl sulphuric acid esters.
  • N-substituted pipera zines of the general Formula V are N-methyl-, N -ethyl-, N-n-propyl-, N-fi-hydroxyethyL, N-y-hydroxypropyh, N- fi-hydroxybutyland N.B-acetoxyethyl-piperazine.
  • N-substituted iminostilbenes of the general Formula I can be produced by reacting a piperazinoalkyl-iminostilbene 7 of the general formula -with a reactive ester of and B-bromoethyl acetate.
  • As reactive esters of alcohols of the general Formula VII can be named methyl bromide, methyl iodide, ethyl bromide, ethyl iodide, n-butyl bromide, dimethyl sulphate, diethyl sulphate, ,B-chlorethyl acetate
  • alkylene oxides can be named ethylene oxide and propylene oxide.
  • the new N-substituted iminostilbenes of the general Formula I can also be produced by reacting an iminostilbene of the general Formula II, possibly in the presence of an acid binding agent, or reacting a metal compound of such an irninostilbene, with phosgene, re-
  • compounds of the general Formula I in which R is a lower hydroxyalkyl radical can be esterified to form compounds of the same general Formula I in which R is a lower alkanoyloxyalkyl radical.
  • the tertiary bases form salts with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methane sulphonic acid,
  • ethane sulphonic acid ethane disulphonic acid
  • acetic acid citric acid, malic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, benzoic acid and phthalic acid.
  • Some of these salts are water soluble.
  • Example I 9.7 parts of iminostilbene are dissolved in 150 parts by volume of anh. benzene and the base from parts of 1- ('y-chloropropyl) -4-methyl-pipera zine dihydrochloride in 300 parts by volume of benzene is added. A suspen sion of 2.5 parts of sodium amide in toluene is added dropwise at 40-50 while stirring Well. The reaction mixture is stirred for 3 hours at 50 and then boiled under reflux for 16 hours. It is then cooled to room temperature and water is added. The benzene phase is removed and shaken out several times with diluted acetic acid. The combined acetic acid extracts are made al kaline with concentrated caustic soda lye.
  • Example 2 13 parts of 3.7-dichloro-iminostilbene are dissolved in 300 parts by volume of anh. benzene and the solution of the base from 14 parts of l-(v-chloro-propyl)-4-methy1- piperazine dihydrochloride in 200 parts by volume of anh. benzene is added. 2.5 parts of sodium amide, sus
  • Example 3 19 parts of iminostilbene and 20 parts of 1-chloro-3- bromopropane are dissolved in 800 parts by volume of anh. benzene and 4.4 parts of sodium amide intoluene are added dropwise while stirring strongly, the addition being made within half an hour at 50. On completion of the dropwise addition, the whole is stirred for another 3 hours at 50-60 and then refluxedfor 3 hours. After cooling, water is added to the reaction mixture and the benzene phase is separated, washed with water, dried and concentrated. The oily residue is dissolved in 400 parts by volume of petroleum ether, any undissolved iminostilbene is filtered off and the solvent is evaporated. Oily N-(v-chloropropyl)-iminostilbene remains which, after recrystallisation from anh. ether, melts at 6'7.
  • the dihydrochloride prepared with alcoholic hydrochloric acid melts at 228-230 N-[y-(4 hydroxyethyl-piperazine)-propyl]3.7 dichloroiminostilbene and its dihydrochloride can be produced in an analogous manner.
  • Example 4 1 part of N-[w(4-hydroxyethyl-piperazino)-propyl]- iminostilbene and 5 partes of acetic acid anhydride are refluxed for 4 hours. The excess acetanhydride is evaporated in the vacuum, the residue is dissolved in cold water, the solution is filtered and the filtrate is made alkaline with sodium carbonate solution. The precipitate is dissolved in either, the ether solution is washed with water, dried over sodium sulphate and the solvent is distilled on. The residue is dissolved in petroleum ether, the solution is filtered and the filtrate is concentrated. N-[y-(4-acetoxyethyl-piperazino) -propyl] -iminostilbene is obtained as a yellow oil.
  • N-[' -(4-acetoxyethyl-piperazino) )-propyl]'-3.7-dichloro-iminostilbene and its dihydrochloride are obtained from N-[y-( l-hydroxyethyl piperazinzon -propyl] -3 .7-dichloro-iminostilbene.
  • X represents a member selected from the group consisting of hydrogen and chlorine
  • 'alkylene represents a 26 carbon alkylene chain separating the adjacent nitrogen atoms to which it is attached by at least two carbon atoms
  • R represents a member selected from the group consisting of lower alkyl, lower alkanoyloxyalkyl and lower hydroxyalkyl.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
US832498A 1957-05-09 1959-08-10 5-substituted dibenz[b, f] azepine compounds Expired - Lifetime US3133068A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CH4591057A CH364263A (de) 1957-05-09 1957-05-09 Verfahren zur Herstellung von basisch substituierten Azepinen
CH5833258A CH366542A (de) 1957-05-09 1958-04-15 Verfahren zur Herstellung von basischen Derivaten von Azepinen

Publications (1)

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US3133068A true US3133068A (en) 1964-05-12

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US (1) US3133068A (en(2012))
BE (1) BE567519A (en(2012))
CH (4) CH364263A (en(2012))
DE (1) DE1133729B (en(2012))
FR (1) FR1226426A (en(2012))
GB (1) GB862297A (en(2012))
NL (1) NL103879C (en(2012))

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3947447A (en) * 1974-05-20 1976-03-30 American Hoechst Corporation 5H-aminoacetamido-10,11-dihydrodibenz-[b,f]azepines and immediate precursors

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5599929A (en) * 1994-11-09 1997-02-04 Taro Pharmaceutical Industries Ltd Method for preparing opipramol

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2541211A (en) * 1948-10-15 1951-02-13 Searle & Co Tertiary-aminoalkyl-tetrahydrocarbazoles
US2676966A (en) * 1951-04-04 1954-04-27 Searle & Co Quaternary salts of 9-carbazolealkylamines and 10-acridanalkylamines and methods forpreparing same
US2676971A (en) * 1951-04-21 1954-04-27 Searle & Co Quaternary ammonium derivatives of aminoalkylxanthenes and aminoalkylthiaxanthenes
US2861987A (en) * 1955-12-28 1958-11-25 Cilag Ltd New diphenyl methane- and 1-aza-[2,3:5,6]-dibenzocy cloheptadiene derivatives, theiracid salts and quaternary salts and the production thereof

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NL95693C (en(2012)) * 1955-10-20

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2541211A (en) * 1948-10-15 1951-02-13 Searle & Co Tertiary-aminoalkyl-tetrahydrocarbazoles
US2676966A (en) * 1951-04-04 1954-04-27 Searle & Co Quaternary salts of 9-carbazolealkylamines and 10-acridanalkylamines and methods forpreparing same
US2676971A (en) * 1951-04-21 1954-04-27 Searle & Co Quaternary ammonium derivatives of aminoalkylxanthenes and aminoalkylthiaxanthenes
US2861987A (en) * 1955-12-28 1958-11-25 Cilag Ltd New diphenyl methane- and 1-aza-[2,3:5,6]-dibenzocy cloheptadiene derivatives, theiracid salts and quaternary salts and the production thereof

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3947447A (en) * 1974-05-20 1976-03-30 American Hoechst Corporation 5H-aminoacetamido-10,11-dihydrodibenz-[b,f]azepines and immediate precursors

Also Published As

Publication number Publication date
DE1133729B (de) 1962-07-26
CH364263A (de) 1962-09-15
NL103879C (en(2012)) 1963-02-15
CH366542A (de) 1963-01-15
CH360061A (de) 1962-02-15
GB862297A (en) 1961-03-08
BE567519A (en(2012)) 1958-11-08
CH359143A (de) 1961-12-31
FR1226426A (fr) 1960-07-11

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